Salicylic acid (SA), the major metabolite of aspirin, has been used for centuries for its analgesic, anti-inflammatory, and antipyretic effects (Wu, Circulation 2000, 102, (17), 2022-3). Recently, SA has been found to be beneficial for many other applications such as wound healing, diabetes, arthritis, and cancer treatment (Roseborough et al., J Natl Med Assoc 2004, 96, (1), 108-16; Rumore et al., Ann Pharmacother 2010, 44, (7-8), 1207-21; Yamazaki et al., J Pharm Pharmacol 2002, 54, (12), 1675-9; Perugini et al., J Gastrointest Surg 2000, 4, (1), 24-32, discussion 32-3; and Spitz et al., Biochem Pharmacol 2009, 77, (1), 46-53). As with all pharmaceutical treatments, best results are obtained when SA is maintained at therapeutic levels in the desired area for as long as it is needed (Uhrich et al., Chem Rev 1999, 99, (11), 3181-98). This presents an issue as oral delivery of SA results in systemic delivery and potential gastrointestinal problems, while not maintaining steady SA concentrations (Amann et al., Eur J Pharmacol 2002, 447, (1), 1-9). Localized delivery from polymers can help overcome these problems while also allowing higher localized SA levels than with systemic delivery.
To better control SA release, salicylic acid-based poly(anhydride-esters) (SA-PAEs) were developed in which SA is chemically incorporated into the polymer backbone via a biocompatible linker molecule. The chemical incorporation of SA enables inherent drug loading capacities up to 90% (w/w), with the capacity to physically admix additional drug to obtain even higher loading (Johnson et al., J Biomed Mater Res A 2009, 91, (3), 671-8). SA-PAEs have been designed to fully degrade over a matter of days to many months. These polymers hydrolytically degrade to exhibit near zero-order SA release after an initial lag period, where minimal to no drug is released. The length of the lag period and the subsequent rate of release can be controlled by changing the linker molecule (Prudencio et al., Macromolecules 2005, 38, (16), 6895-6901).
While the SA-PAE release rate can be changed for different applications, the lag period is should be considered for certain applications. For example, a lag period may be beneficial for applications such as bone regeneration where an initial inflammatory response is desired, but localized reduced inflammation is beneficial at a later time point (Mountziaris et al., Tissue Engineering Part B: Reviews 2008, 14, (2), 179-186; and Simon et al., The Journal of Bone and Joint Surgery 2007, 89, (3), 500-511). On the other hand, the lag period could be considered a disadvantage if SA was desired immediately following implantation, as it would be in applications where inflammation is already present (i.e., arthritis and diabetes).
Accordingly, there is a need for sustained release formulations of SA. In particular, there is a need for sustained release formulations of SA which eliminate the lag period.